Despite considerable research, fundamental questions about CFS remain at best partially answered. These questions include its definition, validity, the degree to which it results from genetic versus environmental factors, the nature of the substantial comorbidity observed with other conditions, and the basis of the female preponderance. The overarching aim of this project is to shed light on a number of basic questions about CFS via a large, population-based classical twin study. First, we will collect data on approximately 32,000 adults aged 42-65 years (13,000 complete twin pairs) who are members of the population- based Swedish Twin Registry for persistent fatigue, several overlapping conditions (fibromyalgia, irritable bowel syndrome, tension headache, allergy/eczema, generalized anxiety disorder, and major depression), and a detailed medical history. Second, the medical records of all twins who appear to have CFS-like illness and a subset of those with "CFS-explained" will be requested via an efficient national retrieval system. Following expert review, these individuals will be classified in regard to the CDC CFS criteria. Obtaining these unique data will allow us to address a set of critical questions regarding CFS. First, we will estimate the prevalence of CFS and its common comorbidities (fibromyalgia, irritable bowel syndrome, tension headache, allergy/eczema, generalized anxiety disorder, and major depression) in one of the largest samples yet studied. Second, we will use a variety of multivariate techniques to derive an empirical typology of prolonged fatigue and to assess how this typology compares to the CFS definition. Third, we will quantify the genetic and environmental sources of variation for CFS and its comorbid conditions. Fourth, critically, we will examine the influence of gender on these sources of variation. Finally, we will analyze the patterns of comorbidity between CFS and fibromyalgia, irritable bowel syndrome, tension headache, allergy/eczema, generalized anxiety disorder, and major depression using multivariate twin analyses and thereby to estimate the extent of overlap between the shared and unique genetic and environmental sources of variation. In concert with other twin studies being conducted by the investigators and their collaborators, we hope to hasten progress in understanding the etiology of CFS by parallel studies in multiple populations. The current proposal has several unique aims and represents a cost-effective means to extend this work in an epidemiological sample that is arguably the best twin registry in the world.